Osmotic dispensers have heretofore been proposed, each of which is capable of dispensing concentrations of active agent at an osmotically controlled rate over a prolonged period of time.
Typically, these osmotic dispensers are comprised of a first compartment of relatively impervious material containing an active agent and a second compartment or chamber of controlled permeability to water containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water. Such devices are so constructed that, when placed in or functionally exposed to* a hypotonic aqueous environment, water is absorbed therefrom by osmosis and diffuses into the solution contained in the second compartment. As the water flows into the second compartment, the solution contained therein and in certain instances the compartment itself increase in volume, thus generating, either directly or indirectly, mechanical pressure or force on the active agent containing first compartment. The said first compartment is provided with any suitable dispensing head for releasing its active agent content to the exterior of the dispenser and individually is of a construction that its active volume is inversely responsive to the pressure thus exerted, i.e., is of such construction that, in use, the volume of same diminishes in a direct proportion to and as a consequence of increase in volume in the said second compartment. Hence, the rate and amount of release of the active agent are directly proportional to the change in volume in the second compartment, but inversely proportional to the volume change in the first. That is, as the water flows into the device, the second compartment increases in volume generating corresponding pressure or force on the first, either directly or indirectly, as by transmitting pressure against a separate or common wall FNT *By "functionally exposed to" it is intended that, for example, such devices may be provided with their own self-contained water supply or separate water compartment, as in the first mentioned Rose and Nelson publication, supra.
member thereof, which wall member is yielding to such pressure, or by biasing a movable barrier into or against the first compartment or a wall member defining the same. The volume of said first compartment is thus constantly diminished and active agent is correspondingly continuously squeezed thereout at an osmotically controlled rate over a prolonged period of time.
In the aforementioned related applications, the disclosures of which are hereby incorporated by reference and are relied upon, there are described and claimed several osmotic active agent dispensers of the immediately above type.
For example, in Higuchi copending application, Ser. No. 106,131 filed Jan. 13, 1971, now U.S. Pat. No. 3,760,805, an osmotic dispenser is comprised of a water permeable housing member, advantageously rigid, confining a first flexible bag of relatively impervious material containing the active agent, advantageously a drug, preferably in a gel, paste or other semisolid state (albeit a solution or a concentrated solution of active agent will sometimes suffice), and a second bag of controlled permeability to moisture containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water. The said first and second bags are disposed within the said water permeable housing member or porous shell such that water permeates from the environment through the porous shell or housing and migrates by osmosis into the solution contained in the second bag. The solution in the second bag increases in volume, exerting mechanical force on the active agent containing first bag, which mechanical force in turn ejects the active agent out of the apparatus. For purposes of permitting the active agent to be squeezed out of the said first flexible bag, same is provided with any suitable active agent release means or dispensing head to the exterior of the device, e.g., long plastic tubing extending through the porous shell, or ductlike fine tubule connections therethrough.
Higuchi and Leeper copending application, Ser. No. 106,130, filed Jan. 13, 1971, now U.S. Pat. No. 3,732,865, relates to an osmotic dispenser comprised of a first compartment of relatively impervious material containing an active agent and a second compartment containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water Separating the said first from the said second compartment, and defining a wall member common to each of said compartments, is a sliding or movable barrier of impervious material. The enclosure, whether of integral construction or not, defining the remainder of the second compartment, wherein the osmotic motive force of the dispenser is developed, is at least in part comprised of membrane which exhibits controlled permeability to water. When placed in a hypotonic aqueous environmet, water, by osmosis, is absorbed therefrom through the membrane and diffuses into the solution contained in the said second compartment. As the water flows into the second compartment, the solution contained therein increases in volume exerting corresponding pressure behind the movable barrier divider. Such pressure serves to drive the said barrier forward and into the active agent compartment thus diminishing the volume of same, and which sliding barrier in turn ejects the active agent out of the apparatus at an osmotically controlled rate over a prolonged period of time. For purposes of permitting the active agent to be squeezed out of the first compartment, same also is provided with any suitable dispensing head or active agent release means to the exterior of the device, for example, capillary ducts therethrough. A further feature of this invention resides in an osmotic active agent dispenser comprised of a plurality of capsule half shells, similar in shape to pharmaceutical hard gelatin half shells, with a first and a second half shell being securedly affixed in capsular configuration, and a third half shell frictionally disposed in such capsule but free to slidably move therein. The said capsule is thereby divided into the two compartments with the third half shell defining the wall member common to each of same.
And Leeper copending application, Ser. No. 106,132, filed Jan. 13, 1971, now U.S. Pat. No. 3,760,806, describes an osmotic dispenser comprised of a first helical compartment of relatively impervious material containing an active agent and a second helical compartment containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water. The two helical compartments are interconnected so as to define a continuous helix. Separating the first helical compartment from the second helical compartment, and defining a wall member common to each of said compartments, is a sliding or movable barrier of impervious material capable of traversing the helix, advantageously a plastic or glass ball separator. The enclosure, whether of integral construction or not, defining the remainder of the second compartment wherein the osmotic motive force of the dispenser is developed, is at least in part comprised of membrane material which exhibits controlled permeability to water. When placed in a hypotonic aqueous environment, water, by osmosis, is absorbed therefrom through the membrane and diffuses into the solution contained in the second compartment. As the water flows into the second compartment, the solution contained therein increases in volume exerting corresponding pressure behind the movable barrier divider. Such pressure serves to drive the said barrier forward and into the active agent compartment thus diminishing the volume of the same, and which sliding or rolling barrier in turn ejects the active agent out of the apparatus at an osmotically controlled rate over a prolonged period of time. For the purpose of permitting the active agent to be squeezed out of the first compartment, the same is provided at its terminal point with any suitable dispensing head or active agent release means to the exterior of the device, for example, a capillary duct therethrough. A further feature of this invention resides in an osmotic active agent dispenser comprised of a dispenser according to the foregoing description enveloped by a relatively rigid, highly permeable housing member. The housing member serves both as a protective means for the dispenser and also to restrict expansion of the dispenser due to internal pressure. Alternatively, such expansion may be in and of itself restricted by means of any suitable bond or tie member.
The osmotic active agent dispenser described in Higuchi and Leeper copending application, Ser. No. 106,161, filed Jan. 13, 1971, is comprised of a chamber having controlled permeability to water and containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water, said chamber housing a flexible bag of relatively impervious material containing an active agent and provided with means or dispensing head for releasing said active agent to the exterior of the dispenser. The flexible bag is disposed within the said housing chamber such that as water permeates from the external environment through the permeable walls of the chamber and migrates or diffuses by osmosis into the solution contained therein, same increases in volume thereby generating mechanical compressing or deflating force on the flexible bag, which force in turn ejects the active agent out of the apparatus at an osmotically controlled rate over a prolonged period of time.
The osmotic dispenser proposed in the Rose and Nelson article, supra, too is capable of delivering drug solution at a relatively constant rate. This injector consists of three compartments and a clamp to hold a semi-permeable membrane. The motive force of the injector depends on the osmotic pressure developed by a saturated aqueous solution of Congo red against water. This solution is contained in a partially collapsed rubber compartment and is separated from a second water compartment by the semi-permeable cellophane membrane. The partially collapsed bag is placed in a glass ampoule, with the drug compartment of the device being defined by the space between the Congo red bag and the glass ampoule. The ampoule is also provided with drug release means and when the drug compartment is charged with a drug solution water will move by osmosis into the Congo red solution, thus expanding the rubber compartment and providing the mechanical force to eject the drug out of the apparatus.
The compartment or chamber of the aforesaid osmotic active agent dispensers containing the solution of the osmotically effective solute, wherein the osmotic motive force of the respective devices is developed, is at least in part comprised of membrane which exhibits controlled permeability to water. Such membrane can be formed from a wide variety of materials permeable or semi-permeable to solvent (water) but not to solute, i.e., those suitable for the construction of an osmotic cell. Typical membranes are isotropic membranes such as unplasticized cellulose acetate, plasticized cellulose acetate, reinforced cellulose acetate, cellulose di- and triacetate, ethyl cellulose; anisotropic reverse osmosis membranes which typically are made of cellulose acetate; silicone rubbers, polyurethanes, natural rubber, and hydrolyzed ethylene/vinyl acetate copolymers. Isotropic membranes have less water permeability than do the anisotropic membranes. Also, with both types of membranes, increasing the acetate content of the cellulose acetate polymer decreases the water permeability. In devices, the surface areas of the membranes of which are relatively limited, it will be preferred to use semi-permeable membranes allowing relatively rapid water transmission. Thus, in such embodiments the anisotropic membranes are the preferred. For drug depot applications as heretofore described, the membranes are also biologically inert, non-irritating to body tissues and non-allergenic. So too in such applications are the other materials from which the topic dispensers are fabricated. For best results, the membrane should be substantially impermeable to passage of the osmotically effective solute so as to prevent loss thereof.
In the osmotic dispenser proposed by Rose and Nelson, supra, the active agent is employed in the form of a solution. Consequently, there result several disadvantages as regards the handling of such osmotic devices, e.g., spillage and loss of active ingredient, as well as in their storage capabilities since drug containing solutions generally have a relatively short shelf life, and many chemical substances on prolonged storage in a dissolved state undergo chemical deterioration. Furthermore, the use of solutions in osmotic devices places an absolute upper limit on the concentration of active agent that can be administered from a given volume of composition. This latter limitation is of great importance when overall size limitations of such devices are considered. Moreover, drug or other active agent solutions exhibit the deleterious tendency to be released from an osmotic device by simple leaching.